Our overall goal is to understand the process of the generation of long-term humoral immunity. Long-lived plasma cells and memory B cells are the primary cellular components of long term humoral immunity, and as such are critically important for protection against many infectious diseases and are key components of the protection afforded by most vaccines. Germinal centers are the critical sites for the development of long term humoral immunity in the form of antigen-specific memory B cells and long-lived plasma cells. CD4 T cells are essential for germinal center function. Therefore it is vital to understand the role of CD4 T cells in germinal centers to understand how to better generate long term humoral immunity to viruses. Importantly, we now have an excellent system to examine this process, since we have shown that SAP (SLAM-associated protein) plays a central role in CD4 T cell help at the germinal center stage for the development of long term humoral immunity after a viral infection (Crotty et al., Nature 2003; Crotty and colleagues J. Immunology 2007). We also know that this critical function for SAP is conserved in humans. The experiments proposed herein are designed to answer pivotal questions regarding T cell help to B cells and the generation of long-term humoral immunity. This knowledge will illuminate a central process of adaptive immunity (the germinal center reaction and the generation of immunological memory) and help accelerate vaccine discovery (as a primary goal of vaccines is generation of memory B cells and long-term antibody production). Our studies focus heavily on antiviral immune responses because 1) SAP-deficiency results in an lethal susceptibility to infectious disease in humans, demonstrating that SAP is a crucial mediator of antiviral immune responses, and 2) the purpose of virtually all vaccine development is the prevention/control of infectious diseases. Aim 1. What are the functional characteristics of germinal center / follicular helper CD4 T cells (TFH)? How do they drive strong antiviral antibody responses and the development of immunological memory? Why is SAP critical? We want to understandin cellular and molecular detailwhat, where, and how CD4 T cells in the follicle drive, sustain, and control the germinal center reaction and the generation of long-lived plasma cells and memory B cells. Aim 2. SAP and ICOS: What is the link and what are their respective roles in germinal center development? Aim 3. Which SLAM-family receptor on CD4 T cells is critical for signaling germinal center help? Given the varied inputs and outputs of the SAP signaling pathway, it is unclear what SAP-dependent receptor is critical for signaling the downstream T cell help functions key for germinal center help.